Approccio terapeutico alla malattia avanzata nel tumore del colon-retto
Roberto Moretto
Azienda Ospedaliero-Universitaria Pisana Università di Pisa
Perugia
16 Gennaio 2016
Cytotoxics
+
Biologic
Bevacizumab Cetuximab Panitumumab
Up today the most common choice as 1st-line tx
Are doublets the only chemo backbone option?
MONOCHEMO DOUBLETS TRIPLET
How to choose?
Resectability
(aka treatment’s aim)
Key message from 2012 ESMO clinical guidelines
Schmoll et al, Ann Oncol ’12
How to choose?
Resectability
(aka treatment’s aim)
RAS status
Key message from 1000000….
debates following FIRE-3 and PEAK
ASCO/ESMO 2014: CALGB 80405
Lenz et al, ESMO Congress 2014
How to choose?
Resectability
(aka treatment’s aim)
RAS status
Key message from 2014 ESMO clinical guidelines
Van Cutsem et al, Ann Oncol ’14
How to choose?
Resectability
(aka treatment’s aim)
PATIENT’S ASSESSMENT
(age, PS, patients’ expectations and motivation, logistics)
RAS status
Van Cutsem et al, ESMO WCGIC ‘15
10 | ADVANCE ONLINE PUBLICATION www.nature.com/ nrclinonc
Sequencing of therapy
The substantial influence of first-line sys- temic treatment in dictating the prognosis of patients with mCRC is well known. As a consequence of the availability of a growing number of effective second-line options, how the choice of first-line therapy might affect the outcome of the second and further lines of treatment is an increasingly crucial question. At present, only retrospective data,
mainly collected from trials of first-line treat- ments after evidence of disease progression, are available.74 New insights into this ques- tion might be provided by strategy trials that are designed to prospectively compare subsequent lines of treatment. In the Italian TRIBE2 study,75 for example, 654 patients with mCRC will be randomly assigned to receive either first-line FOLFOXIRI plus bevacizumab followed by reintroduction of
FOLFOXIRI plus bevacizumab at disease progression or FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab upon disease progression (Table 3). The objectives of this trial are to optimize the use of first- line FOLFOXI RI plus bevacizumab and to fully answer the question whether the upfront use of the triplet actually improves survival, as compared with the sequential use of oxaliplatin- based and irinotecan- based doublets. In the French STRATEGIC-1 study,76 474 patients with RAS-wild-type disease will be randomly assigned to first- line FOLFIRI plus cetuximab followed by an oxaliplatin-based doublet plus bevaci- zumab in the second-line, or to first-line oxaliplatin-based doublet plus bevacizumab followed by an irinotecan-based doublet plus bevacizumab as the second-line treat- ment, followed by an anti-EGFR mAb with or without irinotecan in the third-line. The objective of this trial is to investigate the best sequencing of the available targeted agents in the RAS-wild-type mCRC setting.
Conclusions
The choice of the first-line treatment marks a crucial step in the therapeutic route for every patient with mCRC. The ‘fine tuning’
of this choice is now possible thanks to the availability of a growing number of effective treatment options. Not only does the identifi- cation of the best molecularly targeted agent for each patient deserve consideration, but nowadays robust evidence from clinical trials enables clinicians to also modulate the intensity of the first-line chemotherapy, thus marking an important step forward on the path to delivering personalized treat- ment. For this purpose, the evaluation of the patient’s condition, rather than RAS muta- tional status or potential tumour resect- ability, stands at the top of every treating physician’s personal checklist when tailoring the best upfront treatment for every patient with mCRC. Many controversial issues remain open: mainly related to the duration of the induction treatment, the role of main- tenance therapy (especially with regard to anti-EGFR mAbs), and the best s equencing of cytotoxic and targeted agents following disease progression. Further efforts from translational research are needed in order to disclose molecular mechanisms of intrin- sic and acquired resist ance to the available drugs and drug combinations. Only properly designed clinical trials, including compre- hensive translational end points, will be able to consolidate and improve on the notable achievements made in the past decade.
Nature Reviews | Clinical Oncology Assess patient
No
No
No
Yes
Yes
Yes Fluoropyrimidine monotherapy +
bevacizumab, or personalized low-intensity treatment
Assess RAS and (BRAF* ) status
Assess RAS and BRAF status Previous oxaliplatin-based
adjuvant therapy?
Mutated
Mutated Wild-type
Wild-type‡ Rapid response needed?
Doublet chemotherap y + bevacizumab
Triplet chemotherapy + bevacizumab Doublet chemotherapy
+ anti-EGFR agent
No Yes
Appropriate candidate for combination chemotherap y?
Appropriate for triplet chemotherap y?
Figure 1 | Algorithm for personalized allocation of first-line treatments in patients with mCRC.
We propose this algorithm based on the currently available evidence discussed in this manuscript.
Patients with unresectable mCRC should undergo thorough clinical assessment to determine their eligibility for combination chemotherapy (FOLFOX, FOLFIRI, or XELOX doublets, or the FOLFOXIRI triplet), mainly based on their age, ECOG performance status, comorbidities, and personal motivation and expectations. Patients who are not deemed to be appropriate candidates for such regimens can be treated with a fluoropyrimidine plus bevacizumab or with a personalized low-intensity treatment.
Patients who are fit for doublet, but not triplet, chemotherapy can additionally receive either
bevacizumab or an anti-EGFR monoclonal antibody (either cetuximab or panitumumab), according to tumour RAS (and BRAF) status and whether a clinical response is required, mainly based on the need to achieve rapid and deep tumour shrinkage for symptom relief or to pursue a secondary resection. With regard to the influence of BRAF status in this setting (* ), subgroup analyses of trials of doublet chemotherapy plus anti-EGFR agents show modest benefit from the addition of the anti- EGFR agent in patients with tumours harbouring BRAF mutations, and very limited available data seem to suggest no interaction of BRAF status with the efficacy of bevacizumab; thus, treatment choice should consider the different toxicity profiles of doublet chemotherapy plus either
bevacizumab or an anti-EGFR agent. Patients who are deemed appropriate candidates for triplet therapy, mainly based on their ECOG performance status and age, can be treated with FOLFOXIRI plus bevacizumab, independent of mutation status; however, patients with tumours that are wild-type for RAS and BRAF could be offered doublet chemotherapy plus an EGFR-targeted antibody instead.
No direct comparisons between therapy with doublet chemotherapy plus an anti-EGFR agent and triplet chemotherapy plus bevacizumab in RAS/ BRAF-wild-type patients (‡) are available, and the treatment choice should consider the different toxicity profiles of these regimens. Abbreviations:
ECOG, Eastern Cooperative Oncology Group; FOLFIRI, 5-fluorouracil, folinic acid, and irinotecan;
FOLFOX, 5-fluorouracil, folinic acid, and oxaliplatin; FOLFOXIRI, 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan; mCRC, metastatic colorectal cancer; XELOX, capecitabine plus oxaliplatin.
PERSPECTIVES
© 2015 Macmillan Publishers Limited. All rights reserved
1st line treatment of mCRC: an evidence-based algorithm
Cremolini et al, Nat Rev Clin Oncol ‘15
Cunnigham et al., Lancet Oncol 2013
Monochemo plus bev: AVEX trial
Stratification factors:
ECOG PS (0–1 vs 2) Geographic region
Key inclusion criteria – ECOG PS 0–2
– Prior adjuvant chemotherapy allowed if completed >6 month before inclusion
– Not optimal candidates for a combination chemotherapy with irinotecan or oxaliplatin
R
280 mCRC pts 1st line mCRC AGE 70 years
Capecitabine
Capecitabine + bev
Cunningham et al, Lancet Oncol ‘13
AVEX trial: PFS and OS
PFS – primary endpoint
OS
Cunningham D. et al, Lancet Oncol ‘13
AVEX - Toxicity Profile
AE%
Cape + bev (n=134)
Cape (n=136)
Bleeding/hemorrhage
– 0.7
Hypertension
2.2 1.5
Venous thromboembolic events
8.2 4.4
Proteinuria
1.5 –
Arterial thromboembolic events
3.7 1.5
Wound healing complications
– –
Pulmonary hemorrhage/hemoptysis
– 0.7
Fistulae
– –
Congestive heart failure
– 0.7
GI perforation
– –
RPLS
– –
Sastre et al, Oncologist 2012
Monochemo + anti-EGFR
67 mCRC pts 1st line mCRC AGE 70 years
Capecitabine + cet
ITT population N = 67
KRAS wt population N = 29
Response Rate
31.8% 48.3%
Median PFS, mos
7.1 8.4
Median OS, mos
16.1 18.8
Phase II
“Without present or imminent symptoms and limited risk for rapid deterioration, the aim is rather prevention of tumour progression and prolongation of life with minimal treatment burden…an escalation strategy may start with an FP in combination with bevacizumab”
Van Cutsem et al, Ann Oncol 2014
Monotherapy…when?
In most cases we cannot estimate how “indolent” the disease is
MONOTHERAPY is a NEED more than a CHOICE
10 | ADVANCE ONLINE PUBLICATION www.nature.com/ nrclinonc
Sequencing of therapy
The substantial influence of first-line sys- temic treatment in dictating the prognosis of patients with mCRC is well known. As a consequence of the availability of a growing number of effective second-line options, how the choice of first-line therapy might affect the outcome of the second and further lines of treatment is an increasingly crucial question. At present, only retrospective data,
mainly collected from trials of first-line treat- ments after evidence of disease progression, are available.74 New insights into this ques- tion might be provided by strategy trials that are designed to prospectively compare subsequent lines of treatment. In the Italian TRIBE2 study,75 for example, 654 patients with mCRC will be randomly assigned to receive either first-line FOLFOXIRI plus bevacizumab followed by reintroduction of
FOLFOXIRI plus bevacizumab at disease progression or FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab upon disease progression (Table 3). The objectives of this trial are to optimize the use of first- line FOLFOXI RI plus bevacizumab and to fully answer the question whether the upfront use of the triplet actually improves survival, as compared with the sequential use of oxaliplatin- based and irinotecan- based doublets. In the French STRATEGIC-1 study,76 474 patients with RAS-wild-type disease will be randomly assigned to first- line FOLFIRI plus cetuximab followed by an oxaliplatin-based doublet plus bevaci- zumab in the second-line, or to first-line oxaliplatin-based doublet plus bevacizumab followed by an irinotecan-based doublet plus bevacizumab as the second-line treat- ment, followed by an anti-EGFR mAb with or without irinotecan in the third-line. The objective of this trial is to investigate the best sequencing of the available targeted agents in the RAS-wild-type mCRC setting.
Conclusions
The choice of the first-line treatment marks a crucial step in the therapeutic route for every patient with mCRC. The ‘fine tuning’
of this choice is now possible thanks to the availability of a growing number of effective treatment options. Not only does the identifi- cation of the best molecularly targeted agent for each patient deserve consideration, but nowadays robust evidence from clinical trials enables clinicians to also modulate the intensity of the first-line chemotherapy, thus marking an important step forward on the path to delivering personalized treat- ment. For this purpose, the evaluation of the patient’s condition, rather than RAS muta- tional status or potential tumour resect- ability, stands at the top of every treating physician’s personal checklist when tailoring the best upfront treatment for every patient with mCRC. Many controversial issues remain open: mainly related to the duration of the induction treatment, the role of main- tenance therapy (especially with regard to anti-EGFR mAbs), and the best s equencing of cytotoxic and targeted agents following disease progression. Further efforts from translational research are needed in order to disclose molecular mechanisms of intrin- sic and acquired resist ance to the available drugs and drug combinations. Only properly designed clinical trials, including compre- hensive translational end points, will be able to consolidate and improve on the notable achievements made in the past decade.
Nature Reviews | Clinical Oncology Assess patient
No
No
No
Yes
Yes
Yes Fluoropyrimidine monotherapy +
bevacizumab, or personalized low-intensity treatment
Assess RAS and (BRAF* ) status
Assess RAS and BRAF status Previous oxaliplatin-based
adjuvant therapy?
Mutated
Mutated Wild-type
Wild-type‡ Rapid response needed?
Doublet chemotherap y + bevacizumab
Triplet chemotherapy + bevacizumab Doublet chemotherapy
+ anti-EGFR agent
No Yes
Appropriate candidate for combination chemotherap y?
Appropriate for triplet chemotherap y?
Figure 1 | Algorithm for personalized allocation of first-line treatments in patients with mCRC.
We propose this algorithm based on the currently available evidence discussed in this manuscript.
Patients with unresectable mCRC should undergo thorough clinical assessment to determine their eligibility for combination chemotherapy (FOLFOX, FOLFIRI, or XELOX doublets, or the FOLFOXIRI triplet), mainly based on their age, ECOG performance status, comorbidities, and personal motivation and expectations. Patients who are not deemed to be appropriate candidates for such regimens can be treated with a fluoropyrimidine plus bevacizumab or with a personalized low-intensity treatment.
Patients who are fit for doublet, but not triplet, chemotherapy can additionally receive either
bevacizumab or an anti-EGFR monoclonal antibody (either cetuximab or panitumumab), according to tumour RAS (and BRAF) status and whether a clinical response is required, mainly based on the need to achieve rapid and deep tumour shrinkage for symptom relief or to pursue a secondary resection. With regard to the influence of BRAF status in this setting (* ), subgroup analyses of trials of doublet chemotherapy plus anti-EGFR agents show modest benefit from the addition of the anti- EGFR agent in patients with tumours harbouring BRAF mutations, and very limited available data seem to suggest no interaction of BRAF status with the efficacy of bevacizumab; thus, treatment choice should consider the different toxicity profiles of doublet chemotherapy plus either
bevacizumab or an anti-EGFR agent. Patients who are deemed appropriate candidates for triplet therapy, mainly based on their ECOG performance status and age, can be treated with FOLFOXIRI plus bevacizumab, independent of mutation status; however, patients with tumours that are wild-type for RAS and BRAF could be offered doublet chemotherapy plus an EGFR-targeted antibody instead.
No direct comparisons between therapy with doublet chemotherapy plus an anti-EGFR agent and triplet chemotherapy plus bevacizumab in RAS/ BRAF-wild-type patients (‡) are available, and the treatment choice should consider the different toxicity profiles of these regimens. Abbreviations:
ECOG, Eastern Cooperative Oncology Group; FOLFIRI, 5-fluorouracil, folinic acid, and irinotecan;
FOLFOX, 5-fluorouracil, folinic acid, and oxaliplatin; FOLFOXIRI, 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan; mCRC, metastatic colorectal cancer; XELOX, capecitabine plus oxaliplatin.
PERSPECTIVES
© 2015 Macmillan Publishers Limited. All rights reserved
1st line treatment of mCRC: an evidence-based algorithm
Cremolini et al, Nat Rev Clin Oncol ‘15
TRIBE Study Design
Primary endpoint: Progression Free Survival Participating Centers: 34 Italian Oncology Units
First patient in: July 2008 – Last patient in: May 2011
Loupakis et al, NEJM 2014
FOLFIRI + bev, median PFS : 9.7 mos FOLFOXIRI + bev, median PFS : 12.1 mos
HR: 0.75 [0.62-0.90]
p=0.003
Primary endpoint - PFS
Loupakis et al, NEJM 2014
Secondary endpoint - OS
MEDIAN F-UP 48.1 mos (74% events) FOLFIRI + bev: N = 256 / Died = 200 FOLFOXIRI + bev: N = 252 / Died = 174
FOLFIRI + bev, median OS : 25.8 mos FOLFOXIRI + bev, median OS : 29.8 mos
HR: 0.80 [0.65-0.98]
p=0.030
Cremolini et al, Lancet Oncol 2015
Secondary endpoint: Response rate
Best Response, %
FOLFIRI + bev N = 256
FOLFOXIRI + bev
N = 252 p
Complete Response 3% 5%
Partial Response 50% 60%
Response Rate 53% 65% 0.006
Stable Disease 32% 25%
Progressive Disease 11% 6%
Not Assessed 4% 4%
Loupakis et al, NEJM 2014
TRIBE study: Early response and Depth of response
Modified by Cremolini et al., Ann Onc 2015
FOLFOXIRI + BV FOLFIRI + BV
-100 -80 -60 -40 -20 0 20 40 60 80
-100 -80 -60 -40 -20 0 20 40 60 80
Median time to nadir:
FOLFIRI + BV 4.3 m FOLFOXIRI + BV 3.5 m
P=0.0005 62.7%
51.9%
FOLFOXIRI + Bev
FOLFIRI + Bev 441 pts (87% of the ITT)
Tumor Shrinkage ≥20% at 8 weeks
P=0.025
Consistent results with FOLFOXIRI plus bev
FOIB N = 57
TRIBE N=252
OPAL N=97
Response Rate
77% 65% 64%
Disease Control Rate
100% 90% 87%
Median PFS, mos
13.1 12.3 11.1
Median OS, mos
30.9 29.8 32.2
Masi et al, Lancet Oncol ‘10, Cremolini et al, Lancet Oncol ‘15, Stein et al, Br J Canc ‘15
✓ Is it just for potentially resectable patients?
FOLFOXIRI+bev: common questions
TRIBE study: patients’ characteristics
N=508
Characteristic, % patients
FOLFIRI + bev N = 256
FOLFOXIRI + bev N = 252
Sex (M / F)
61 / 39 60 / 40
Median Age (range)
60 (29 – 75) 61 (29 – 75)
ECOG PS (0 / 1-2)
89 / 11 90 / 10
Synchronous Metastases (Y / N)
81 / 19 79 / 21
Prior Adjuvant CT (Y / N)
13 / 87 13 / 87
Primary Tumor Site (right / left / NR)
24 / 70 / 6 35 / 60 / 5
Number Metastatic Sites (1 / >1)24 / 76 31 / 69
Liver Only Disease (Y / N)
18 / 82 23 / 77
Resected Primary (Y / N)
65 / 35 69 / 31
Kohne score (low / interm / high / NE)
41 / 44 / 11 / 4 43 / 44 / 7 / 6
Loupakis et al., NEJM 2014
FOLFIRI + bev Arm A N = 256
FOLFOXIRI + bev Arm B
N = 252
p
Liver-only subgroup
N = 46 N = 59Secondary surgery with radical intent
41% 39% 1.000R0 secondary surgery
28% 32% 0.823TRIBE study: secondary resection rate
TRIBE – Secondary endpoint: Resection rate
Loupakis et al., NEJM 2014
Triplet plus bev in liver limited disease: OLIVIA trial
Gruenberger et al, Ann Oncol 2014
80 mCRC pts:
liver-only unresectable disease
FOLFOX+Bev
N=39R 1:1
FOLFOXIRI+Bev
N=41Primary endpoint: Radical Resection Rate
mFOLFOX-6 + bev N = 39
FOLFOXIRI + bev N = 41
Overall Response Rate 62% 81% p= 0.061
R0/R1/R2 surgery 49% 61% p=0.327
R0 surgery 23% 49% 0.017
PFS (median) 11.5 18.6 HR: 0.43 (0.26–0.72)
RFS (median) 8.1 17.1 HR: 0.31 (0.12–0.75)
OS (median) 32.2 Not reached -
Phase II random
✓ Is it just for potentially resectable patients?
FOLFOXIRI+bev: common questions
The triplet plus bev is a good option independently of the intent to pursue
a secondary resection
✓ Is it just for potentially resectable patients?
✓ What do you think about toxicities?
FOLFOXIRI+bev: common questions
Loupakis et al., NEJM 2014
TRIBE study - safety profile
Personal Considerations
Stomatitis and diarrhea
are (slightly) increased in frequency…
… are not worse in seriousness
… are not treated differently than with FOLFOX or FOLFIRI
… are not longer in duration
Personal Considerations
G3-4 Neutropenia is increased in frequency, but
… is usually short-lasting
G-CSF is not recommended as primary prophylaxis.
It can be used in secondary prophylaxis in case of:
• Previous febrile neutropenia;
• Previous G4 neutropenia (if ≥5 days) or
• >2 delays of planned therapy due to neutropenia
… is rarely complicated
✓ Is it just for potentially resectable patients?
✓ What do you think about toxicities?
FOLFOXIRI+bev: common questions
✓ TRIPLET+bev: is it for every single patient?
Subgroup analyses of PFS
Loupakis et al., NEJM 2014
TRIBE: Key Eligibility Criteria
Histologically proven adenocarcinoma
Unresectable (locally assessed) mCRC not pre-treated for mets
Measurable disease according to RECIST 1.0
Age 18-75
ECOG PS ≤ 2 (ECOG PS = 0 if age = 71-75 years)
Adjuvant oxa-containing chemotherapy allowed if more than 12 months elapsed between the end of adjuvant and first relapse
Adequate bone marrow, liver and renal functions
Loupakis et al., NEJM 2014
✓ Is it just for potentially resectable patients?
✓ What do you think about toxicities?
FOLFOXIRI+bev: common questions
✓ What about the RAS story and TRIBE’s molecular subgroups?
✓ TRIPLET+bev: is it for every single patient?
N
FOLFIRI + bev Median OS
FOLFOXIRI + bev
Median OS
HR [95% CI] p
ITT population 508 25.8 29.8 0.80 [0.65-0.98] 0.030 RAS and BRAF
evaluable 357 24.9 28.6 0.84 [0.66-1.07] 0.159
RAS and BRAF wt 93 33.5 41.7 0.77 [0.46-1.27]
0.522*
RAS mutated 236 23.9 27.3 0.88 [0.65-1.18]
BRAF mutated 28 10.7 19.0 0.54 [0.24-1.20]
* p for interaction
Treatment effect in molecular subgroups - OS
Cremolini et al, Lancet Oncol ’15
Events Median 28 41.7 months 32 33.5 months 88 27.3 months 93 23.9 months 14 19.0 months 11 10.7 months RAS and BRAF wild-type – arm B RAS and BRAF wild-type – arm A RAS mutant – arm B RAS mutant– arm A
BRAF mutant – arm B BRAF mutant– arm A
Treatment effect in molecular subgroups - OS
Cremolini et al, Lancet Oncol ’15
FOLFOXIRI+bev: common questions
✓ Is it just for potentially resectable patients?
✓ What do you think about toxicities?
✓ What about the RAS story and TRIBE’s molecular subgroups?
✓ TRIPLET+bev: is it for every single patient?
✓ How important is it ”to add bev”?
0 6 12 18 24 30 36 42 48 54 60 0
25 50 75 100
P e rc e n t F re e o f P ro g re s s io n
FOLFOXIRI: median PFS: 9.8 mos
FOLFOXIRI+Bev: median PFS: 12.3 mos
Adj HR*: 0.76 [0.59-0.97], p=0.027
*propensity score-adjusted analysis
FOLFOXIRI plus bev: does bev matter?
✓ What do you do after?
FOLFOXIRI+bev: common questions
✓ Is it just for potentially resectable patients?
✓ What do you think about toxicities?
✓ What about the RAS story and TRIBE’s molecular subgroups?
✓ TRIPLET+bev: is it for every single patient?
✓ How important is it ”to add bev”?
First-line treatment over time in Arm B
Progression
-fr ee su rviv al p robab ility
F-up time (months)
FOLFIRI + bev FOLFOXIRI + bev
0–6 mos
I N D U C T I O N
6–12 mos
MA I N T E N
…
FOLFOXIRI + bev
5-FU “only” + bev
6 mos median OXALIPLATIN and
IRINOTECAN-free
interval
Maintenance - Combined analysis: any Tx vs No-Tx
Progression-free survival
Favours active tx. Favours no tx.
Arnold D. et al, ASCO 2014
Overall survival
✓ DATA on MAINTENANCE
✓ EFFICACY of BEV BEYOND PROGRESSION A new challenge for the FOLFOXIRI+bev concept
✓ EFFICACY of FIRST-LINE TRIPLET
✓ LACK of DATA for SEQUENTIAL PRE-
PLANNED STRATEGIES…
TRIBE-2 trial
R 1:1
FOLFOX + bev*
FOLFOXIRI + bev*
PD1
PD1
5FU/bev
5FU/bev
FOLFIRI + bev*
FOLFOXIRI + bev*
5FU/bev
5FU/bev
*all repeated for 8 cycles (4 months) followed by maintenance with 5FU/bev until PD
Primary endpoint: PFS2 – Target Accrual 654 – Accrual up to Jan 15, 2016: 201
PD2
PD2
10 | ADVANCE ONLINE PUBLICATION www.nature.com/ nrclinonc
Sequencing of therapy
The substantial influence of first-line sys- temic treatment in dictating the prognosis of patients with mCRC is well known. As a consequence of the availability of a growing number of effective second-line options, how the choice of first-line therapy might affect the outcome of the second and further lines of treatment is an increasingly crucial question. At present, only retrospective data,
mainly collected from trials of first-line treat- ments after evidence of disease progression, are available.74 New insights into this ques- tion might be provided by strategy trials that are designed to prospectively compare subsequent lines of treatment. In the Italian TRIBE2 study,75 for example, 654 patients with mCRC will be randomly assigned to receive either first-line FOLFOXIRI plus bevacizumab followed by reintroduction of
FOLFOXIRI plus bevacizumab at disease progression or FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab upon disease progression (Table 3). The objectives of this trial are to optimize the use of first- line FOLFOXI RI plus bevacizumab and to fully answer the question whether the upfront use of the triplet actually improves survival, as compared with the sequential use of oxaliplatin- based and irinotecan- based doublets. In the French STRATEGIC-1 study,76 474 patients with RAS-wild-type disease will be randomly assigned to first- line FOLFIRI plus cetuximab followed by an oxaliplatin-based doublet plus bevaci- zumab in the second-line, or to first-line oxaliplatin-based doublet plus bevacizumab followed by an irinotecan-based doublet plus bevacizumab as the second-line treat- ment, followed by an anti-EGFR mAb with or without irinotecan in the third-line. The objective of this trial is to investigate the best sequencing of the available targeted agents in the RAS-wild-type mCRC setting.
Conclusions
The choice of the first-line treatment marks a crucial step in the therapeutic route for every patient with mCRC. The ‘fine tuning’
of this choice is now possible thanks to the availability of a growing number of effective treatment options. Not only does the identifi- cation of the best molecularly targeted agent for each patient deserve consideration, but nowadays robust evidence from clinical trials enables clinicians to also modulate the intensity of the first-line chemotherapy, thus marking an important step forward on the path to delivering personalized treat- ment. For this purpose, the evaluation of the patient’s condition, rather than RAS muta- tional status or potential tumour resect- ability, stands at the top of every treating physician’s personal checklist when tailoring the best upfront treatment for every patient with mCRC. Many controversial issues remain open: mainly related to the duration of the induction treatment, the role of main- tenance therapy (especially with regard to anti-EGFR mAbs), and the best s equencing of cytotoxic and targeted agents following disease progression. Further efforts from translational research are needed in order to disclose molecular mechanisms of intrin- sic and acquired resist ance to the available drugs and drug combinations. Only properly designed clinical trials, including compre- hensive translational end points, will be able to consolidate and improve on the notable achievements made in the past decade.
Nature Reviews | Clinical Oncology Assess patient
No
No
No
Yes
Yes
Yes Fluoropyrimidine monotherapy +
bevacizumab, or personalized low-intensity treatment
Assess RAS and (BRAF* ) status
Assess RAS and BRAF status Previous oxaliplatin-based
adjuvant therapy?
Mutated
Mutated Wild-type
Wild-type‡ Rapid response needed?
Doublet chemotherap y + bevacizumab
Triplet chemotherapy + bevacizumab Doublet chemotherapy
+ anti-EGFR agent
No Yes
Appropriate candidate for combination chemotherap y?
Appropriate for triplet chemotherap y?
Figure 1 | Algorithm for personalized allocation of first-line treatments in patients with mCRC.
We propose this algorithm based on the currently available evidence discussed in this manuscript.
Patients with unresectable mCRC should undergo thorough clinical assessment to determine their eligibility for combination chemotherapy (FOLFOX, FOLFIRI, or XELOX doublets, or the FOLFOXIRI triplet), mainly based on their age, ECOG performance status, comorbidities, and personal motivation and expectations. Patients who are not deemed to be appropriate candidates for such regimens can be treated with a fluoropyrimidine plus bevacizumab or with a personalized low-intensity treatment.
Patients who are fit for doublet, but not triplet, chemotherapy can additionally receive either
bevacizumab or an anti-EGFR monoclonal antibody (either cetuximab or panitumumab), according to tumour RAS (and BRAF) status and whether a clinical response is required, mainly based on the need to achieve rapid and deep tumour shrinkage for symptom relief or to pursue a secondary resection. With regard to the influence of BRAF status in this setting (* ), subgroup analyses of trials of doublet chemotherapy plus anti-EGFR agents show modest benefit from the addition of the anti- EGFR agent in patients with tumours harbouring BRAF mutations, and very limited available data seem to suggest no interaction of BRAF status with the efficacy of bevacizumab; thus, treatment choice should consider the different toxicity profiles of doublet chemotherapy plus either
bevacizumab or an anti-EGFR agent. Patients who are deemed appropriate candidates for triplet therapy, mainly based on their ECOG performance status and age, can be treated with FOLFOXIRI plus bevacizumab, independent of mutation status; however, patients with tumours that are wild-type for RAS and BRAF could be offered doublet chemotherapy plus an EGFR-targeted antibody instead.
No direct comparisons between therapy with doublet chemotherapy plus an anti-EGFR agent and triplet chemotherapy plus bevacizumab in RAS/ BRAF-wild-type patients (‡) are available, and the treatment choice should consider the different toxicity profiles of these regimens. Abbreviations:
ECOG, Eastern Cooperative Oncology Group; FOLFIRI, 5-fluorouracil, folinic acid, and irinotecan;
FOLFOX, 5-fluorouracil, folinic acid, and oxaliplatin; FOLFOXIRI, 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan; mCRC, metastatic colorectal cancer; XELOX, capecitabine plus oxaliplatin.
PERSPECTIVES
© 2015 Macmillan Publishers Limited. All rights reserved
1st line treatment of mCRC: an evidence-based algorithm
Cremolini et al, Nat Rev Clin Oncol ‘15
10 | ADVANCE ONLINE PUBLICATION www.nature.com/ nrclinonc
Sequencing of therapy
The substantial influence of first-line sys- temic treatment in dictating the prognosis of patients with mCRC is well known. As a consequence of the availability of a growing number of effective second-line options, how the choice of first-line therapy might affect the outcome of the second and further lines of treatment is an increasingly crucial question. At present, only retrospective data,
mainly collected from trials of first-line treat- ments after evidence of disease progression, are available.74 New insights into this ques- tion might be provided by strategy trials that are designed to prospectively compare subsequent lines of treatment. In the Italian TRIBE2 study,75 for example, 654 patients with mCRC will be randomly assigned to receive either first-line FOLFOXIRI plus bevacizumab followed by reintroduction of
FOLFOXIRI plus bevacizumab at disease progression or FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab upon disease progression (Table 3). The objectives of this trial are to optimize the use of first- line FOLFOXI RI plus bevacizumab and to fully answer the question whether the upfront use of the triplet actually improves survival, as compared with the sequential use of oxaliplatin- based and irinotecan- based doublets. In the French STRATEGIC-1 study,76 474 patients with RAS-wild-type disease will be randomly assigned to first- line FOLFIRI plus cetuximab followed by an oxaliplatin-based doublet plus bevaci- zumab in the second-line, or to first-line oxaliplatin-based doublet plus bevacizumab followed by an irinotecan-based doublet plus bevacizumab as the second-line treat- ment, followed by an anti-EGFR mAb with or without irinotecan in the third-line. The objective of this trial is to investigate the best sequencing of the available targeted agents in the RAS-wild-type mCRC setting.
Conclusions
The choice of the first-line treatment marks a crucial step in the therapeutic route for every patient with mCRC. The ‘fine tuning’
of this choice is now possible thanks to the availability of a growing number of effective treatment options. Not only does the identifi- cation of the best molecularly targeted agent for each patient deserve consideration, but nowadays robust evidence from clinical trials enables clinicians to also modulate the intensity of the first-line chemotherapy, thus marking an important step forward on the path to delivering personalized treat- ment. For this purpose, the evaluation of the patient’s condition, rather than RAS muta- tional status or potential tumour resect- ability, stands at the top of every treating physician’s personal checklist when tailoring the best upfront treatment for every patient with mCRC. Many controversial issues remain open: mainly related to the duration of the induction treatment, the role of main- tenance therapy (especially with regard to anti-EGFR mAbs), and the best s equencing of cytotoxic and targeted agents following disease progression. Further efforts from translational research are needed in order to disclose molecular mechanisms of intrin- sic and acquired resist ance to the available drugs and drug combinations. Only properly designed clinical trials, including compre- hensive translational end points, will be able to consolidate and improve on the notable achievements made in the past decade.
Nature Reviews | Clinical Oncology Assess patient
No
No
No
Yes
Yes
Yes Fluoropyrimidine monotherapy +
bevacizumab, or personalized low-intensity treatment
Assess RAS and (BRAF* ) status
Assess RAS and BRAF status Previous oxaliplatin-based
adjuvant therapy?
Mutated
Mutated Wild-type
Wild-type‡ Rapid response needed?
Doublet chemotherap y + bevacizumab
Triplet chemotherapy + bevacizumab Doublet chemotherapy
+ anti-EGFR agent
No Yes
Appropriate candidate for combination chemotherap y?
Appropriate for triplet chemotherap y?
Figure 1 | Algorithm for personalized allocation of first-line treatments in patients with mCRC.
We propose this algorithm based on the currently available evidence discussed in this manuscript.
Patients with unresectable mCRC should undergo thorough clinical assessment to determine their eligibility for combination chemotherapy (FOLFOX, FOLFIRI, or XELOX doublets, or the FOLFOXIRI triplet), mainly based on their age, ECOG performance status, comorbidities, and personal motivation and expectations. Patients who are not deemed to be appropriate candidates for such regimens can be treated with a fluoropyrimidine plus bevacizumab or with a personalized low-intensity treatment.
Patients who are fit for doublet, but not triplet, chemotherapy can additionally receive either
bevacizumab or an anti-EGFR monoclonal antibody (either cetuximab or panitumumab), according to tumour RAS (and BRAF) status and whether a clinical response is required, mainly based on the need to achieve rapid and deep tumour shrinkage for symptom relief or to pursue a secondary resection. With regard to the influence of BRAF status in this setting (* ), subgroup analyses of trials of doublet chemotherapy plus anti-EGFR agents show modest benefit from the addition of the anti- EGFR agent in patients with tumours harbouring BRAF mutations, and very limited available data seem to suggest no interaction of BRAF status with the efficacy of bevacizumab; thus, treatment choice should consider the different toxicity profiles of doublet chemotherapy plus either
bevacizumab or an anti-EGFR agent. Patients who are deemed appropriate candidates for triplet therapy, mainly based on their ECOG performance status and age, can be treated with FOLFOXIRI plus bevacizumab, independent of mutation status; however, patients with tumours that are wild-type for RAS and BRAF could be offered doublet chemotherapy plus an EGFR-targeted antibody instead.
No direct comparisons between therapy with doublet chemotherapy plus an anti-EGFR agent and triplet chemotherapy plus bevacizumab in RAS/ BRAF-wild-type patients (‡) are available, and the treatment choice should consider the different toxicity profiles of these regimens. Abbreviations:
ECOG, Eastern Cooperative Oncology Group; FOLFIRI, 5-fluorouracil, folinic acid, and irinotecan;
FOLFOX, 5-fluorouracil, folinic acid, and oxaliplatin; FOLFOXIRI, 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan; mCRC, metastatic colorectal cancer; XELOX, capecitabine plus oxaliplatin.
PERSPECTIVES
© 2015 Macmillan Publishers Limited. All rights reserved
1st line treatment of mCRC: an evidence-based algorithm
Cremolini et al, Nat Rev Clin Oncol ‘15
10 | ADVANCE ONLINE PUBLICATION www.nature.com/ nrclinonc
Sequencing of therapy
The substantial influence of first-line sys- temic treatment in dictating the prognosis of patients with mCRC is well known. As a consequence of the availability of a growing number of effective second-line options, how the choice of first-line therapy might affect the outcome of the second and further lines of treatment is an increasingly crucial question. At present, only retrospective data,
mainly collected from trials of first-line treat- ments after evidence of disease progression, are available.74 New insights into this ques- tion might be provided by strategy trials that are designed to prospectively compare subsequent lines of treatment. In the Italian TRIBE2 study,75 for example, 654 patients with mCRC will be randomly assigned to receive either first-line FOLFOXIRI plus bevacizumab followed by reintroduction of
FOLFOXIRI plus bevacizumab at disease progression or FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab upon disease progression (Table 3). The objectives of this trial are to optimize the use of first- line FOLFOXI RI plus bevacizumab and to fully answer the question whether the upfront use of the triplet actually improves survival, as compared with the sequential use of oxaliplatin- based and irinotecan- based doublets. In the French STRATEGIC-1 study,76 474 patients with RAS-wild-type disease will be randomly assigned to first- line FOLFIRI plus cetuximab followed by an oxaliplatin-based doublet plus bevaci- zumab in the second-line, or to first-line oxaliplatin-based doublet plus bevacizumab followed by an irinotecan-based doublet plus bevacizumab as the second-line treat- ment, followed by an anti-EGFR mAb with or without irinotecan in the third-line. The objective of this trial is to investigate the best sequencing of the available targeted agents in the RAS-wild-type mCRC setting.
Conclusions
The choice of the first-line treatment marks a crucial step in the therapeutic route for every patient with mCRC. The ‘fine tuning’
of this choice is now possible thanks to the availability of a growing number of effective treatment options. Not only does the identifi- cation of the best molecularly targeted agent for each patient deserve consideration, but nowadays robust evidence from clinical trials enables clinicians to also modulate the intensity of the first-line chemotherapy, thus marking an important step forward on the path to delivering personalized treat- ment. For this purpose, the evaluation of the patient’s condition, rather than RAS muta- tional status or potential tumour resect- ability, stands at the top of every treating physician’s personal checklist when tailoring the best upfront treatment for every patient with mCRC. Many controversial issues remain open: mainly related to the duration of the induction treatment, the role of main- tenance therapy (especially with regard to anti-EGFR mAbs), and the best s equencing of cytotoxic and targeted agents following disease progression. Further efforts from translational research are needed in order to disclose molecular mechanisms of intrin- sic and acquired resist ance to the available drugs and drug combinations. Only properly designed clinical trials, including compre- hensive translational end points, will be able to consolidate and improve on the notable achievements made in the past decade.
Nature Reviews | Clinical Oncology Assess patient
No
No
No
Yes
Yes
Yes Fluoropyrimidine monotherapy +
bevacizumab, or personalized low-intensity treatment
Assess RAS and (BRAF* ) status
Assess RAS and BRAF status Previous oxaliplatin-based
adjuvant therapy?
Mutated
Mutated Wild-type
Wild-type‡ Rapid response needed?
Doublet chemotherap y + bevacizumab
Triplet chemotherapy + bevacizumab Doublet chemotherapy
+ anti-EGFR agent
No Yes
Appropriate candidate for combination chemotherap y?
Appropriate for triplet chemotherap y?
Figure 1 | Algorithm for personalized allocation of first-line treatments in patients with mCRC.
We propose this algorithm based on the currently available evidence discussed in this manuscript.
Patients with unresectable mCRC should undergo thorough clinical assessment to determine their eligibility for combination chemotherapy (FOLFOX, FOLFIRI, or XELOX doublets, or the FOLFOXIRI triplet), mainly based on their age, ECOG performance status, comorbidities, and personal motivation and expectations. Patients who are not deemed to be appropriate candidates for such regimens can be treated with a fluoropyrimidine plus bevacizumab or with a personalized low-intensity treatment.
Patients who are fit for doublet, but not triplet, chemotherapy can additionally receive either
bevacizumab or an anti-EGFR monoclonal antibody (either cetuximab or panitumumab), according to tumour RAS (and BRAF) status and whether a clinical response is required, mainly based on the need to achieve rapid and deep tumour shrinkage for symptom relief or to pursue a secondary resection. With regard to the influence of BRAF status in this setting (* ), subgroup analyses of trials of doublet chemotherapy plus anti-EGFR agents show modest benefit from the addition of the anti- EGFR agent in patients with tumours harbouring BRAF mutations, and very limited available data seem to suggest no interaction of BRAF status with the efficacy of bevacizumab; thus, treatment choice should consider the different toxicity profiles of doublet chemotherapy plus either
bevacizumab or an anti-EGFR agent. Patients who are deemed appropriate candidates for triplet therapy, mainly based on their ECOG performance status and age, can be treated with FOLFOXIRI plus bevacizumab, independent of mutation status; however, patients with tumours that are wild-type for RAS and BRAF could be offered doublet chemotherapy plus an EGFR-targeted antibody instead.
No direct comparisons between therapy with doublet chemotherapy plus an anti-EGFR agent and triplet chemotherapy plus bevacizumab in RAS/ BRAF-wild-type patients (‡) are available, and the treatment choice should consider the different toxicity profiles of these regimens. Abbreviations:
ECOG, Eastern Cooperative Oncology Group; FOLFIRI, 5-fluorouracil, folinic acid, and irinotecan;
FOLFOX, 5-fluorouracil, folinic acid, and oxaliplatin; FOLFOXIRI, 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan; mCRC, metastatic colorectal cancer; XELOX, capecitabine plus oxaliplatin.
PERSPECTIVES
© 2015 Macmillan Publishers Limited. All rights reserved
1st line treatment of mCRC: an evidence-based algorithm
Cremolini et al, Nat Rev Clin Oncol ‘15
RR PFS OS
CET/PA
N BEV CET/PA
N BEV CET/PA
N BEV
FIRE-3 N=400
RR 1 ° endpoint
65% 59% 10.3 10.2 33.1 25.0
P=0.18 HR=0.97 HR=0.70, P=.006
NEGATIVE NEGATIVE POSITIVE
CALGB 80405 N=526
OS 1 ° endpoint
69% 54% 11.4 11.3 32.0 31.2
P<0.01 HR=1.10 HR=0.90
POS/NEG NEGATIVE NEGATIVE
PEAK N=170
PFS 1 ° endpoint
65% 60% 12.8 10.1 36.9 28.9
P=0.86 0.029 0.15
“NEGATIVE” “POSITIVE” “NEGATIVE”
Head to Head trials in RAS wt mCRC
Stintzing et al., Lancet Oncol ‘14 Lenz et al, ESMO 2014 Rivera et al, ECC 2015
FIRE-3 and PEAK: Early tumor shrinkage
Adapted from Stintzing et al., ESMO 2014 Rivera et al., ASCO GI 2015
330 RAS wt pts ETS≥20% at 6 weeks
p=0.0005 68.2%
49.1%
bev cet
154 RAS wt pts
ETS ≥20% at 8 weeks
p=0.122 75%
62%
bev pan
FIRE-3 PEAK
FIRE-3: Depth of response
Stintzing et al, ESMO ‘14
p<0.0001
PEAK: Depth of response
Rivera et al, ECC ‘15
CI, confidence interval; DoR, duration of response;
DpR, depth of response; ETS, early tumor shrinkage;
HR, hazard ratio; TTR, time to response
Tumor Response-Related Efficacy – RAS WT Population
Panitumumab + mFOLFOX6 (n = 88) Bevacizumab + mFOLFOX6 (n = 82)
Median DoR, months (95% CI) 11.4 (10.0, 16.3) 9.0 (7.6, 9.5)
HR (95% CI); P value 0.59 (0.39, 0.88); 0.011
Median TTR, months (95% CI) 2.3 (1.9, 3.7) 3.8 (2.1, 5.7)
HR (95% CI); P value 1.19 (0.81, 1.74); 0.37
Median DpR, months (Q1, Q3) 65.0 (45.7, 89.5) 46.3 (29.5, 63.3)
P value 0.0018
Mean (95% CI) Percentage Change From Baseline In Tumor Load Over Time
0
M e a n C h a n g e F r o m B a s e li n e , %
-20 -40 -60 -80 -100
0 8 16 24 32 40 48 56 64 72 80
Pmab + mFOLFOX6 88 80 70 63 53 42 42 27 25 17 17 Bmab + mFOLFOX6 81 74 66 57 45 36 26 22 13 11 8
Weeks
Bmab + mFOLFOX6 Pmab + mFOLFOX6
Rivera F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2014.
p=0.0018
10 | ADVANCE ONLINE PUBLICATION www.nature.com/ nrclinonc
Sequencing of therapy
The substantial influence of first-line sys- temic treatment in dictating the prognosis of patients with mCRC is well known. As a consequence of the availability of a growing number of effective second-line options, how the choice of first-line therapy might affect the outcome of the second and further lines of treatment is an increasingly crucial question. At present, only retrospective data,
mainly collected from trials of first-line treat- ments after evidence of disease progression, are available.74 New insights into this ques- tion might be provided by strategy trials that are designed to prospectively compare subsequent lines of treatment. In the Italian TRIBE2 study,75 for example, 654 patients with mCRC will be randomly assigned to receive either first-line FOLFOXIRI plus bevacizumab followed by reintroduction of
FOLFOXIRI plus bevacizumab at disease progression or FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab upon disease progression (Table 3). The objectives of this trial are to optimize the use of first- line FOLFOXI RI plus bevacizumab and to fully answer the question whether the upfront use of the triplet actually improves survival, as compared with the sequential use of oxaliplatin- based and irinotecan- based doublets. In the French STRATEGIC-1 study,76 474 patients with RAS-wild-type disease will be randomly assigned to first- line FOLFIRI plus cetuximab followed by an oxaliplatin-based doublet plus bevaci- zumab in the second-line, or to first-line oxaliplatin-based doublet plus bevacizumab followed by an irinotecan-based doublet plus bevacizumab as the second-line treat- ment, followed by an anti-EGFR mAb with or without irinotecan in the third-line. The objective of this trial is to investigate the best sequencing of the available targeted agents in the RAS-wild-type mCRC setting.
Conclusions
The choice of the first-line treatment marks a crucial step in the therapeutic route for every patient with mCRC. The ‘fine tuning’
of this choice is now possible thanks to the availability of a growing number of effective treatment options. Not only does the identifi- cation of the best molecularly targeted agent for each patient deserve consideration, but nowadays robust evidence from clinical trials enables clinicians to also modulate the intensity of the first-line chemotherapy, thus marking an important step forward on the path to delivering personalized treat- ment. For this purpose, the evaluation of the patient’s condition, rather than RAS muta- tional status or potential tumour resect- ability, stands at the top of every treating physician’s personal checklist when tailoring the best upfront treatment for every patient with mCRC. Many controversial issues remain open: mainly related to the duration of the induction treatment, the role of main- tenance therapy (especially with regard to anti-EGFR mAbs), and the best s equencing of cytotoxic and targeted agents following disease progression. Further efforts from translational research are needed in order to disclose molecular mechanisms of intrin- sic and acquired resist ance to the available drugs and drug combinations. Only properly designed clinical trials, including compre- hensive translational end points, will be able to consolidate and improve on the notable achievements made in the past decade.
Nature Reviews | Clinical Oncology Assess patient
No
No
No
Yes
Yes
Yes Fluoropyrimidine monotherapy +
bevacizumab, or personalized low-intensity treatment
Assess RAS and (BRAF* ) status
Assess RAS and BRAF status Previous oxaliplatin-based
adjuvant therapy?
Mutated
Mutated Wild-type
Wild-type‡ Rapid response needed?
Doublet chemotherap y + bevacizumab
Triplet chemotherapy + bevacizumab Doublet chemotherapy
+ anti-EGFR agent
No Yes
Appropriate candidate for combination chemotherap y?
Appropriate for triplet chemotherap y?
Figure 1 | Algorithm for personalized allocation of first-line treatments in patients with mCRC.
We propose this algorithm based on the currently available evidence discussed in this manuscript.
Patients with unresectable mCRC should undergo thorough clinical assessment to determine their eligibility for combination chemotherapy (FOLFOX, FOLFIRI, or XELOX doublets, or the FOLFOXIRI triplet), mainly based on their age, ECOG performance status, comorbidities, and personal motivation and expectations. Patients who are not deemed to be appropriate candidates for such regimens can be treated with a fluoropyrimidine plus bevacizumab or with a personalized low-intensity treatment.
Patients who are fit for doublet, but not triplet, chemotherapy can additionally receive either
bevacizumab or an anti-EGFR monoclonal antibody (either cetuximab or panitumumab), according to tumour RAS (and BRAF) status and whether a clinical response is required, mainly based on the need to achieve rapid and deep tumour shrinkage for symptom relief or to pursue a secondary resection. With regard to the influence of BRAF status in this setting (* ), subgroup analyses of trials of doublet chemotherapy plus anti-EGFR agents show modest benefit from the addition of the anti- EGFR agent in patients with tumours harbouring BRAF mutations, and very limited available data seem to suggest no interaction of BRAF status with the efficacy of bevacizumab; thus, treatment choice should consider the different toxicity profiles of doublet chemotherapy plus either
bevacizumab or an anti-EGFR agent. Patients who are deemed appropriate candidates for triplet therapy, mainly based on their ECOG performance status and age, can be treated with FOLFOXIRI plus bevacizumab, independent of mutation status; however, patients with tumours that are wild-type for RAS and BRAF could be offered doublet chemotherapy plus an EGFR-targeted antibody instead.
No direct comparisons between therapy with doublet chemotherapy plus an anti-EGFR agent and triplet chemotherapy plus bevacizumab in RAS/ BRAF-wild-type patients (‡) are available, and the treatment choice should consider the different toxicity profiles of these regimens. Abbreviations:
ECOG, Eastern Cooperative Oncology Group; FOLFIRI, 5-fluorouracil, folinic acid, and irinotecan;
FOLFOX, 5-fluorouracil, folinic acid, and oxaliplatin; FOLFOXIRI, 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan; mCRC, metastatic colorectal cancer; XELOX, capecitabine plus oxaliplatin.
PERSPECTIVES
© 2015 Macmillan Publishers Limited. All rights reserved
1st line treatment of mCRC: an evidence-based algorithm
Cremolini et al, Nat Rev Clin Oncol ‘15
